Effect of tyrosine kinase inhibitors on stemness in normal and chronic myeloid leukemia cells
| Autor: | Aurélie Bedel, François Moreau-Gaudry, Mahon Fx, Isabelle Moranvillier, François Béliveau, H. de Verneuil, Sandrine Dabernat, Isabelle Lamrissi-Garcia, L Charaf, Bruno Cardinaud |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cancer Research MAP Kinase Signaling System Induced Pluripotent Stem Cells Fusion Proteins bcr-abl Biology 03 medical and health sciences 0302 clinical medicine Leukemia Myelogenous Chronic BCR-ABL Positive hemic and lymphatic diseases Tumor Cells Cultured medicine Humans Induced pluripotent stem cell Protein Kinase Inhibitors neoplasms Myeloid leukemia Imatinib Hematology Protein-Tyrosine Kinases medicine.disease Embryonic stem cell respiratory tract diseases Haematopoiesis Leukemia 030104 developmental biology Oncology 030220 oncology & carcinogenesis Immunology Neoplastic Stem Cells Cancer research Stem cell Tyrosine kinase medicine.drug |
| Zdroj: | Leukemia. 31:65-74 |
| ISSN: | 1476-5551 0887-6924 |
| Popis: | Although tyrosine kinase inhibitors (TKIs) efficiently cure chronic myeloid leukemia (CML), they can fail to eradicate CML stem cells (CML-SCs). The mechanisms responsible for CML-SC survival need to be understood for designing therapies. Several previous studies suggest that TKIs could modulate CML-SC quiescence. Unfortunately, CML-SCs are insufficiently available. Induced pluripotent stem cells (iPSCs) offer a promising alternative. In this work, we used iPSCs derived from CML patients (Ph+). Ph+ iPSC clones expressed lower levels of stemness markers than normal iPSCs. BCR-ABL1 was found to be involved in stemness regulation and ERK1/2 to have a key role in the signaling pathway. TKIs unexpectedly promoted stemness marker expression in Ph+ iPSC clones. Imatinib also retained quiescence and induced stemness gene expression in CML-SCs. Our results suggest that TKIs might have a role in residual disease and confirm the need for a targeted therapy different from TKIs that could overcome the stemness-promoting effect caused by TKIs. Interestingly, a similar pro-stemness effect was observed in normal iPSCs and hematopoietic SCs. These findings could help to explain CML resistance mechanisms and the teratogenic side-effects of TKIs in embryonic cells. |
| Databáze: | OpenAIRE |
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